Nanoparticle formulations of DNA repair inhibitors to improve chemoradiotherapy

描述（由申请人提供）：放化疗是癌症管理中的一种重要治疗模式。鉴于其重要性，肿瘤学的主要研究目标之一是开发药物以进一步提高放化疗的治疗指数。DNA修复抑制剂（DRIs）是一类具有很高应用潜力的药物。然而，DRI的临床转化受到药物递送挑战的阻碍。虽然传统的药物递送方法无法克服这些挑战，但纳米颗粒（NP）药物递送载体的发展提供了前所未有的机会。NPs在肿瘤中的优先积累、在正常组织中的低分布和受控释放特性都是用于化学放射疗法的有利特征。我们的小组是第一个开发NP DRI，NP渥曼青霉素（Wtmn），并证明其在改善放射治疗方面的潜力。我们也是第一个证明NP治疗剂在放化疗中比小分子治疗剂更有效的人之一。我们假设NP递送可以克服药物递送的挑战，并促进放化疗中DRI的临床转化。本申请的总体目标是开发和评价NP DRI用于放化疗。为了设计NP DRIs，我们计划利用非润湿模板中的颗粒复制（PRINT）NP平台，该平台能够制造对尺寸，形状，载药量和药物释放进行精确控制的NP。重要的是，PRINT已经经历了临床开发过程，这将提高快速临床翻译。头颈部鳞状细胞癌（HNSCC）将用作模型疾病，因为放化疗是这种疾病最常见和最有效的治疗方法。我们的申请有三个具体目标。第一个目标将集中在理解和优化关键因素，如药物释放，这可能会影响PRINT NP Wtmn的疗效和毒性。我们的第二个目标将研究在何种程度上共同提供化疗与Wtmn可以改善放化疗。我们的目标是设计可以与Wtmn共同递送多西他赛或顺铂（HNSCC中两种最常用的化疗药物）的PRINT NP。将在HNSCC的小鼠模型中评价这些NP，并与分别给予的化疗和NP Wtmn进行比较。第三个目标是研究聚ADP核糖聚合酶抑制剂（PARPIs）的NP制剂在放化疗中的潜力。PARPI是DRI，已知与化疗和放疗协同作用。这种双重致敏作用为它们在放化疗中提供了独特的潜力。总之，我们的申请旨在应用纳米医学的进步来改善放化疗。我们的工作可以导致NP DRIs用于放化疗的快速临床开发。它可以直接转化为提高治愈率和改善HNSCC和其他难以治疗的癌症患者的生存率。我的长期研究目标是利用开发和利用NP疗法，如DRIs，以改善放化疗治疗模式。

DESCRIPTION (provided by applicant): Chemoradiotherapy is an important treatment paradigm in cancer management. Given its importance, one of the primary research objectives in oncology has been to develop agents to further improve chemoradiotherapy's therapeutic index. One class of agent, the DNA repair inhibitors (DRIs), holds high potential in such application. However, DRIs' clinical translation has been prevented by drug delivery challenges. While traditional drug delivery methods have been unable to overcome these challenges, the development of nanoparticle (NP) drug delivery vehicles offers an unprecedented opportunity. NPs' preferential accumulation in tumors, low distribution in normal tissue, and controlled release properties are all favorable characteristics for applications in chemoradiotherapy. Our group was the first to develop an NP DRI, NP wortmannin (Wtmn), and demonstrated its potential in improving radiotherapy. We are also one of the first to demonstrate that NP therapeutics are more effective than their small molecule counterparts in chemoradiotherapy. We hypothesize that NP delivery can overcome the drug delivery challenges and facilitate the clinical translation of DRIs in chemoradiotherapy. The overall objective of this application is to develop and evaluate NP DRIs for chemoradiotherapy. To engineer NP DRIs, we plan to utilize the Particle Replication in Non-Wetting Templates (PRINT) NP platform, which is capable of fabricating NPs with precise control over size, shape, drug loading and drug release. Importantly, PRINT has undergone the clinical development process, which will enhance rapid clinical translation. Head and neck squamous cell carcinoma (HNSCC) will be used as a model disease since chemoradiotherapy is the most common and effective treatment for this disease. Our application has three specific aims. The first aim will focus on understanding and optimizing the key factors, such as drug release, that can affect PRINT NP Wtmn's efficacy and toxicity. Our second aim will study to the extent which co-delivering a chemotherapeutic with Wtmn can improve chemoradiotherapy. We aim to engineer PRINT NPs that can either co-deliver docetaxel or cisplatin, two mostly commonly used chemotherapeutics in HNSCC, with Wtmn. These NPs will be evaluated in mouse models of HNSCC and compared to chemotherapy and NP Wtmn given separately. The third aim will study NP formulations of poly ADP ribose polymerase inhibitors (PARPIs)'s potential in chemoradiotherapy. PARPIs are DRIs and are known to act synergistically with both chemotherapy and radiotherapy. Such dual sensitization provides them unique potentials in chemoradiotherapy. In summary, our application aims to apply advances in nanomedicine to improving chemoradiotherapy. Our work can lead to the rapid clinical development of NP DRIs for chemoradiotherapy. It can directly translate into increased cure rates and improved survival in patients with HNSCC and other difficult to treat cancers. My long term research goal is to utilize develop and utilize NP therapeutics, such as DRIs, to improve the chemoradiotherapy treatment paradigm.